ES2596803T3 - Progesterone for the prevention of premature birth - Google Patents

Abstract

A medication for use in the treatment or prevention of the onset of premature delivery and subsequent premature birth in a pregnant woman with a short cervix of 1.0 cm to 3.0 cm, where the medication includes progesterone and has been formulated to be administered a dose between 90 mg and 250 mg of progesterone in order to minimize the shortening of the cervix, and where the medication has been formulated for administration vaginally or intravaginally.

Description

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DESCRIPTION

Progesterone for the prevention of premature birth

5 Field of the invention

The present invention describes a method for treating or preventing spontaneous premature birth in pregnant women while improving neonatal health. More specifically, the invention describes a method of treating or preventing the onset of premature delivery that results in premature birth by administering to a pregnant woman an amount of progesterone that is sufficient to prolong pregnancy by delaying shortening.

or the erasure of your cervix. In addition, the invention describes a method of treating or preventing the onset of premature delivery while decreasing neonatal mortality and / or morbidity by administering to an symptomatic pregnant woman of short cervix an effective amount of progesterone to delay delivery and to decrease neonatal mortality and / or morbidity.

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Background of the invention

It is generally known that pregnant women who experience a spontaneous premature birth (NPE) begin with a preterm birth (also referred to here interchangeably as "premature birth") and begin to have regular contractions that cause their cervix to begin to open or become thinner (called dilation and erasure) and soften before reaching approximately 37 weeks of gestation. If a woman gives birth to a baby before 37 weeks, it is typically and conventionally called a premature birth and the baby is considered premature.

25 Premature birth remains one of the most serious problems in obstetrics, with enormous impact on babies, their families, and our society. According to a recent study published by the Institute of Medicine, the incidence of premature birth has increased 33% since 1981, and each year approximately 500,000 women give birth prematurely in the United States alone, causing an annual cost of $ 26 billion. by premature birth to the national health system. It has recently been mentioned that premature births occur in 15% of pregnancies in the developed world and 12.7% of all births in the United States in 2006 and 12.4% of all births in the United States in 2004 See, for example, the use of progesterone to reduce premature birth, American College of Obstetricians and Gynecologists Committee Opinion No. 291, Vol. 102, No. 5, November 2003, pages 1115-1116; Hamilton, B.E., Annal Summary of Vital Statistics: 2005, Pediatrics, Vol. 119, No. 2, February 2007, pages 345-360.

35 A premature birth before 32 weeks of gestation is considered to represent an extremely high risk of morbidity and mortality. In addition, it has been found that a premature birth between 32 and 36 weeks of gestation is especially alarming because large numbers of children are in danger. Premature births account for 60-70% of infant mortality, and are a primary cause of health care expenses both in the perinatal period and throughout the life of surviving babies. Recent advances in modern obstetric and neonatal care have led to greater child survival; However, 55% of newborns with extremely low birth weight (<1000 g) or very premature babies (<28 weeks) who survive middle childhood show evidence of cognitive, educational and clinically significant behavioral impairment.

45 Approximately 20% -30% of premature births are the result of a doctor's decision to cause childbirth for maternal or fetal reasons. The rest of premature births is spontaneous, usually after the onset of premature delivery or rupture of the membranes. Several risk factors for preterm birth have been identified, including: multifetal pregnancy, maternal stress, systemic and intrauterine infection, race, and socioeconomic status. According to the Preterm Prediction Study, a history of previous spontaneous preterm birth is a strong indicator of subsequent premature birth, resulting in an 11-fold increase in risk before 23-27 weeks. Unfortunately, however, risk determination methods that only use historical risk factors have unacceptably low sensitivity and poor predictive value. Complete the history-based risk determination with technology, specifically a determination

55 Ultrasound of the cervix, improves sensitivity and specificity. The ultrasound identification of cervical shortening is correlated with a logarithmic increase in the risk of premature birth. See Iams et al., The length of the cervix and the risk of spontaneous premature delivery, N. Engl. J. Med. 1996; 334: 567-572.

Of the surviving premature babies, many suffer lifelong difficulties, such as cerebral palsy, mental retardation, chronic lung disease, hearing and vision deficits, and learning problems. The more mature a baby is at birth, the more likely it is to survive and the less likely it is to have health-related problems. Premature babies born between 34 and 37 weeks are generally relatively healthy. However, if a woman gives birth before 34 weeks, the risks of adverse effects increase for

65 health and / or medical complications.

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It is generally known that the length of a woman's cervix is a good indication of whether a pregnant woman will experience preterm birth and premature birth. Doctors routinely check a woman's cervix length at the first prenatal visit, so that they can monitor changes in cervical length as the pregnancy progresses. If a woman's cervix is shorter in the middle of pregnancy, it means

5 that the cervix begins to erase (lose weight), and is a good indication that the woman has a higher risk of premature birth.

Cervical shortening, and, to some extent, characteristics such as previous history of premature births, age, ethnicity, body mass index (BMI) and cervical surgery, are known risk factors conventionally related to premature birth. The data confirm an inverse relationship between cervical length and premature birth. In a prospective study of 2915 women who investigated the relationship between short cervical length and premature birth, the researchers found that even a small decrease in cervical length between the 24th and 28th weeks of gestation was associated with an increased risk of premature birth (RR 2.03; 95% CI, 1.28-3.22). See Iams et al., The length of the cervix and the

15 risk of spontaneous premature delivery, N. Engl. J. Med. 1996; 334: 567-572. At 24 weeks, compared to women whose cervical length was greater than 75 percentile of normal, women who had a cervical length of 25 percentile (<3.0 cm) had a relative risk of premature birth of 3.79 (95 % CI, 2.32-6.19); those of 10th percentile (<2.6 cm) had a relative risk of 6.19 (95% CI, 3.84-9.97); the percentile 5 (<2.2 cm) had a relative risk of 9.49 (95% CI, 5.95 to 15.15); and those of percentile 1 (<1.3 cm) had a relative risk of 13.99 (95% cm 7.89 to 24.78). Id. Other studies have determined that cervical length monitoring can contribute to the identification of women at an increased risk of recurrent premature birth. See Spong, C., Prediction and prevention of recurrent spontaneous preterm birth, American College of Obstetricians and Gynecologists, Vol. 110, No. 2, part 1, August 2007, pages 407-408.

25 There is currently no approved therapy to prevent premature births in the United States. See Institute of Medicine Report on Preterm Birth, 2006. Current medical practice for preventive treatments related to short cervix in the early stages of pregnancy involves mechanical / surgical treatments. For example, cervical cerclage is a surgical procedure where the cervix is sewn or closed with stitches, thus physically preventing the cervix from shortening or thinning prematurely. The stitches are then removed, usually approximately week 37, to allow normal dilation of the cervix during delivery. Unfortunately, typical adverse effects associated with cervical cerclage procedures include the risk of premature contractions, cervical dystocia (inability of the cervix to dilate normally during delivery), cervical infections, and other risks generally associated with surgical procedures. In addition, there is controversy about the effectiveness of cerclage in the treatment of short cervix. Several recent studies indicate

35 that this surgical treatment is no better than placebo. Although it is known that cervical length, specifically cervical shortening, is correlated with premature birth, no effective non-surgical intervention is currently known. See Spong, C., pages 407-408. That is, there is currently no accepted medical treatment for the risk factor for premature birth and birth called "short cervix."

He has advocated the administration of progesterone for the prevention of premature birth in some women considered as high risk, although the primary focus has been on patients with a previous history of premature birth. The efficacy of progesterone administered vaginally for the prevention of premature birth in women at especially high risk of preterm birth, particularly women experiencing

45 cervical shortening is far from concrete and is largely unknown. O'Brien et al., For example, determined that prophylactic treatment with vaginal progesterone gel does not effectively reduce the frequency of recurrent premature birth in high-risk women selected for a history of spontaneous premature birth. As indicated by the Committee on Obstetric Practice of the American College of Obstetricians and Gynecologists in the publication “Use of Progesterone to Reduce Preterm Birth,” American College of Obstetricians and Gynecologists Committee Opinion No. 291, Vol. 102, No. 5, November 2003, pages 1115 -1116, the ideal progesterone formulation is, however, unknown.

Da Fonseca et al. (Am. J. Obstet. Gynecol., Vol. 188, No. 2, 2003, pages 419-424) describe the use of vaginal progesterone suppository (100 mg) to delay delivery in a group of pregnant women at risk

55 premature birth. High-risk randomized women in the clinical trial described by da Fonseca were characterized by previous premature birth (90.3%), uterine malformation (5.6%) or incompetent cervix (4.1%).

O. Rust et al. (Am. J. Obstet. Gynecol., Vol. 195, No. 6, Suppl. S, 2006, page S112, Summary 345 of 27th Annual Meeting of the Society of Maternal-Fetal Medicine) describes the effective use of 17P by intramuscular injection in pregnant women with a short cervix (<2.5 cm) for delayed preterm birth.

The use of progesterone for the treatment of all women at risk of premature birth lacks currently unskilled support. Several authors have expressed the need for randomized, properly designed trials, in larger populations to identify the ideal progesterone formulation and dose, and demonstrate a decrease in premature births before 37 weeks and a reduction in

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perinatal morbidity and mortality. See, for example, Dodd et al., Prenatal administration of progesterone for preventing preterm birth, Cochrane Database Syst Rev 2006.

Although there is much debate about the use of progesterone in relation to birth, specifically in relation to

5 gestation period, there is little, or no, conventional technique that analyzes the effects on neonatal populations based on treatments for the prevention of premature birth. The meta-analysis of randomized trials involving women revealed that there may be a reduction in the risk of premature births of less than 37 weeks and 34 weeks. Dodd, J.M. and collaborators, Prenatal administration of progesterone for preventing preterm birth (Review), the Cochrane collaboration, John Wiley Sons, Ltd, 2006, pages 1-36. It is important, however, that there was no statistically significant difference in the occurrence of perinatal death between women who were administered progesterone and who were administered placebo. Dodd, J.M. and collaborators, pages 4-5. In fact, no differences related to neonatal outcomes between the placebo and progesterone groups are reported. Dodd, J.M. and collaborators, pages 4-5; Mackenzie, R. et al., Progesterone for the prevention of preterm birth among women at increased risk: A systematic review and meta-analysis of randomized controlled trials, Journal

15 of Obstetrics and Gynecology, 194, 2006, pages 1234-42.

One study provided information about the prolongation of pregnancy and the morbidity of the child. Lam, F. et al., Evaluation of pregnancy prolongation index (PPI) as a measure of success of obstetric interventions in the prevention of preterm birth and associated morbidities, Jounal of Obstetrics and Gynecology, 192, 2005, 2047

54. However, this study did not provide comparative experimental data between treatment groups and control groups. In addition, this study did not refer to the use of progesterone for treatment or prophylaxis of premature birth. Ultimately, this study was limited to examining neonatal health simply based on gestational age at the time of delivery rather than as a consequence of a treatment / prophylactic agent.

25 Thus, a method of treating or avoiding the onset of preterm birth and the resulting premature birth in pregnant women who have a short cervix, without the adverse health effects that are usually associated with currently known methods, is needed. In addition, beyond the focus on the health of the mother giving birth, there has to be a strong focus on, and an intervention to, improve the neonatal outcome. That is, premature birth is associated with high morbidity and perinatal mortality; and suppression of premature delivery has not been conventionally associated with improved baby outcomes. The conventional technique does not show any direct health benefits of the newborn. Therefore, a treatment and / or prophylaxis is needed in the art to improve natal health, particularly neonatal, for births that take place before term.

35 Summary of the invention

The present invention relates to a medicament for use in the treatment or prevention of the onset of premature delivery and subsequent premature birth in a pregnant woman with a short cervix of 1.0 cm to 3.0 cm, where the medicament includes progesterone and It is formulated to administer a dose between 90 mg and 250 mg of progesterone in order to minimize the shortening of the cervix, and where the medication is formulated for administration vaginally or intravaginally.

Progesterone is preferably administered as a vaginal gel, as a vaginal suppository, as a vaginal cream, or a solid vaginal dosage form (such as a tablet), or by means of a delivery device.

45 inserted into the vagina, such as a cervical ring or other devices generally known in the art.

The present invention also improves neonatal health, that is, morbidity and / or mortality, of those born to women with short cervical length in mid-pregnancy. Infants born to women receiving progesterone treatment and / or prophylaxis are characterized by lower neonatal morbidity and mortality, fewer days in the neonatal intensive care unit (NICU), lower probability of admission to the NICU, or their combination, compared to babies born to mothers who were not given an effective amount of progesterone during pregnancy. In preferred embodiments, progesterone is administered as a vaginal gel. In other additional embodiments, progesterone is administered daily beginning at about the 18th to the 22nd week of gestation until about the 37th week of gestation, preferably during

55 approximately 14 to 19 weeks.

In other embodiments of the present invention, progesterone is administered to a pregnant woman whose cervix is longer than about 1.0 cm and more preferably greater than 1.5 cm, where progesterone is administered to a pregnant woman whose cervix is a length that is less than or equal to about 3.0 cm, preferably less than 2.8 cm and even more preferably less than 2.5 cm.

In the embodiments of the present invention, the progesterone administered can be from any source, including natural or synthetic. In a preferred embodiment, the progesterone is administered by a medicament delivery system that includes progesterone, a crosslinked polycarboxylic acid polymer,

65 inflatable in water, soluble in water, and at least one adjuvant.

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In a preferred embodiment, progesterone is administered daily vaginally. However, administration may be as infrequent as weekly or as frequent as 4 times a day, depending on the characteristics of the formulation. Preferably, the progesterone is administered starting at about the 18th to the 22nd week of gestation until about the 37th week of gestation, or for about 14 to 19

5 weeks, depending on the gestational age at the beginning of the treatment and the date of delivery. In another embodiment, the progesterone is administered starting at about the 16th week of gestation until about the 37th week of gestation, or for about 21 weeks. In other embodiments, progesterone is administered starting at about the time of a positive pregnancy test until about the 37th week of gestation, or beginning at about the 2nd to 4th week of gestation, for approximately 33 to 35 weeks.

Progesterone is preferably administered to a pregnant woman starting as soon as the onset of pregnancy and whose cervix is longer than about 1.0 cm. More preferably, progesterone is administered to a pregnant woman starting as soon as the onset of pregnancy and whose

The cervix has a length of at least about 1.0 cm and at most less than or equal to 2.5 cm or 3.0 cm.

The composition according to the present invention provides an amount of progesterone that is sufficient to minimize or delay the shortening or eradication of the cervix, and possibly softening and dilating.

Brief description of the drawings

Other features and advantages of the invention will be apparent from the description now offered, with reference to the attached figures, which show, by way of example, possible embodiments of the invention.

Figure 1 is a table that includes baseline data regarding participants in a study comparing the efficacy of progesterone in the treatment of premature births in placebo and treatment groups, according to an embodiment of the invention.

Figure 2 is a table illustrating the profile of the participants in the trial, according to an embodiment of the invention.

Figure 3 is a table of participant data with a short cervix of less than 2.8 cm, according to an embodiment of the invention.

Figure 4 is a table that includes cervical length data at week 28 for participants in the placebo and treatment groups, according to an embodiment of the invention.

Figures 5a and 5b illustrate a labor time curve for participants in the placebo and progesterone treatment groups, according to an embodiment of the invention.

Figure 6 is a labor time curve for participants with a cervical base length less than or equal to 3.2 cm, according to an embodiment of the invention.

Figure 7 is a labor time curve for participants with a cervical base length of more than 3.2 cm, according to an embodiment of the invention.

Figure 8 is a labor time curve for participants having a cervical base length less than or equal to 3.0 cm, according to an embodiment of the invention.

Figure 9 is a survival curve, which evaluates preterm birth up to 37 weeks for participants with a cervical length of less than or equal to 3.0 cm, according to an embodiment of the invention.

Figure 10 is a labor time curve for participants having a cervical length of less than 2.8 cm, according to an embodiment of the invention.

Figure 11 is a table summarizing the results of premature birth in study participants with a cervical length of less than 2.8 cm at enrollment, according to an embodiment of the invention.

Figure 12 is a table summarizing the neonatal results in participants with a cervical length of less than 2.8 cm in base, according to an embodiment of the invention.

Figures 13a-e present graphs illustrating results of infants in placebo and treatment patients with a cervical base length ≤ 3.0 cm, according to an embodiment of the present invention.

And Figures 14a-e present graphs illustrating results of infants in placebo and treatment patients 65 with a cervical base length ≤ 2.8 cm, according to an embodiment of the present invention.

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Detailed description of the preferred embodiments

Matter that is not covered by the scope of the claims is not part of the presently claimed invention.

5 In general, it is not known in the field of obstetrics to administer progesterone to a pregnant woman with a short or erased cervix in order to affect cervical dilation and eradication in order to treat or prevent the onset of premature delivery and premature birth. In particular, and to our good knowledge and understanding, there is no literature or other publications that describe or suggest that progesterone can be administered to a pregnant woman with a short cervix to prolong gestation minimizing shortening or eradication of the cervix, and possibly softening and the dilation.

The present invention relates to a medicament for use in the treatment or prevention of the onset of premature delivery and subsequent premature birth in a pregnant woman with a short cervix of 1.0 cm to 3.0 cm,

15 where the medication includes progesterone and is formulated to administer a dose between 90 mg and 250 mg of progesterone in order to minimize the shortening of the cervix, and where the medication is formulated for administration vaginally or intravaginally.

The composition according to the present invention refers to improving neonatal health when administered to pregnant women who have short or erased cervix. In preferred embodiments, the use of progesterone decreases the morbidity and / or mortality of infants born to symptomatic pregnant women with a shortened cervical length. In some variations, infants, whose mother was treated with progesterone, exhibit at least one of: 1) a decrease in days in the neonatal intensive care unit (“NICU”) and 2) lower percentage of admission to the NICU, (that is, a reduction in the percentage of babies admitted to the NICU). The

25 infants born to women who were administered progesterone during pregnancy also exhibit lower incidence of disease and neonatal disorders, such as respiratory distress syndrome (RDS), intraventricular hemorrhage, necrotizing enterocolitis, sepsis, and death, compared to infants at whose mother was not given progesterone during pregnancy. This evidence is indicative of the lower morbidity rate and indicates that fewer babies become ill due to treatment and / or prophylaxis of the pregnant mother who has symptoms of short cervix with progesterone. According to this invention, the treatment and prophylaxis of mothers exhibiting symptoms of the short cervix increases the clinical health of the resulting infant and decreases the frequency of births at or before 37 weeks of gestation.

Embodiments of the present invention suggest that the use of progesterone in patients with short cervix causes

35 a significant reduction in premature births (NPE) of less than or equal to 32 weeks of gestation and / or a significant improvement in selected childhood outcomes. In addition, the embodiments suggest that women who have a short cervical length, preferably less than 3.0 cm, and more preferably less than 2.8 cm, benefit from progesterone therapy as an NPE intervention strategy.

In the sense that it is used here, the term "premature" generally describes human pregnancy that ends at birth before 37 weeks. Consequently, "premature" includes births that take place less than 35 weeks or less or equal to 32 weeks gestation. In addition, another definition of premature delivery includes dilation and / or erasure of the cervix, which is detected by digital examination, associated with persistent uterine contractions before 37 weeks of gestation. In some embodiments explained here, premature delivery is

45 defines as 6 or more uterine contractions per hour accompanied by documented cervical change, cervical dilation greater than 2 cm, cervical erasure greater than 80%, or documented change of cervical erasure greater than 50%.

In the sense that it is used here, short cervix indicates a cervical length of more than 1.0 to 3.5 cm, preferably more than 1.0 to 3.0 cm, more preferably more than 1.0 to 2 , 5 cm, and even more preferably more than 1.0 to 2.0 cm. A cervix of less than 1.0 cm is usually described as an "ultra-short cervix" and is clinically distinguishable from "short cervix." The clinical identification and diagnosis of pregnant women who have a short cervix will be understood by those skilled in the art, and may include methods such as sonographic examination and clinical examination, for example.

55 In the sense that it is used herein, neonatal encompasses children of about 6 months of age or less, preferably about 3 months of age or less, more preferably about 2 months of age or less, and even more preferably about 1 month of age or less. In some embodiments, neonatal is used spanning perinatal, preferably the period after birth.

In the sense that it is used here, the neonatal outcome (here interchangeably referred to as "neonatal health") is measured by the incidence of mortality and morbidity, prevalence, and clinical conditions. For example, health can be directly correlated with the baby's weight. Health may also be inversely related to the incidence of admission to special care (i.e., NICU) at birth, the duration of

65 neonatal hospital stay at birth, the incidence of RDS, the incidence of intraventricular hemorrhage, the incidence of necrotizing enterocolitis, the incidence of sepsis, and the incidence of neonatal death. Those skilled in the art can use other morbidity measures.

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The term "pharmaceutically effective amount" (also referred to herein interchangeably as "an effective amount") has its usual meaning in the art, that is, an amount of a pharmaceutical product that is capable

5 to induce an in vivo and / or clinical response that facilitates management, prophylaxis or therapy. This term may encompass effective therapeutic or prophylactic amounts, or both. In the sense that it is used here, the term "suitable" means suitable for use in mammals, preferably humans, and for the pharmaceutical purposes described herein.

The term "treatment" or "treat" means any treatment of a disease or pathology in a mammal, including: avoiding or protecting against the disease or pathology, that is, causing clinical symptoms to not develop; inhibit the disease or pathology, that is, stop or suppress the development of clinical symptoms; and / or alleviate the disease or pathology, that is, producing the regression of clinical symptoms. In some embodiments, the term "treatment" or "treat" includes improving symptoms, curing or healing, and preventing the development of a

15 given disease.

The term "prophylaxis" is understood as an element of "treatment" to encompass both "prevent" and "suppress", in the sense defined herein. Those skilled in the art will understand that, in human medicine, it is not always possible to distinguish between "prevent" and "suppress" since the last inductive event or events may be unknown, latent, or the patient is not examined until well after appearance of the event or events.

Without being linked to any theory, it is considered that, of all premature births, women who have a short cervix account for approximately 20-30%. The present invention has surprisingly and unexpectedly discovered that the population of women suffering from short cervix among susceptible, predisposed women, or associated with the incidence of premature birth, is sensitive to treatment, prophylaxis and / or other progesterone therapy during pregnancy. to avoid premature births, or to reduce its incidence. Interestingly, there has been much debate in the art regarding the use of progesterone to reduce the incidence of premature birth. Figures 5a and 5b of this application suggest that there are no differences in the gestation period between a population of treated pregnant women receiving progesterone and a control population receiving placebo, where women in both groups have an average base cervical length of more than 3.2 cm Figures 6 and 7 show that the responding population of patients with short cervix (see Figure 6) is hidden in the total population of results (see Figures 5a and 5b) and that patients in the population with longer cervix (see Figure 7) do not show any effect of progesterone similar to the general population (see Figures 5a and 5b). That is, the probability of not giving birth prematurely in the term is generally similar between

35 the two groups. In fact, statistically, the results are so hidden that the prior art does not expect the results we have achieved.

However, an examination of this population of the short cervix (for example, the cervical length is less than or equal to 3.0 cm, as shown in Figure 8, indicates that women receiving progesterone are more likely to give light later during the term of pregnancy than women receiving placebo.In Figure 9, babies born to women who were given progesterone have a greater chance of survival than babies born to women who receive placebo because of a reduction of premature births See Figures 10, 11 and 12. Similar results have been found in women who have cervical lengths of less than 2.8 cm.

The progesterone administered according to the present invention can be a progesterone molecule from any source, including natural or synthetic.

In a preferred embodiment, the progesterone is administered by a medicament delivery system that includes progesterone, a crosslinked, water-swellable, water-soluble polycarboxylic acid polymer, and at least one adjuvant.

In a preferred embodiment, progesterone is administered daily, vaginally. However, administration may be as infrequent as weekly or as frequent as 4 times a day, depending on the characteristics of

55 formulation, including concentration and routes of administration. Preferably, progesterone is administered starting at about the 18th to the 22nd week of gestation until about the 37th week of gestation, or for about 14 to 19 weeks, depending on the gestational age at the start of treatment and the date of delivery. In another embodiment, the progesterone is administered starting at about the 16th week of gestation until about the 37th week of gestation, or for about 21 weeks. In other embodiments, progesterone is administered starting at about the time of a positive pregnancy test until about the 3rd week of gestation, or beginning at about the 2nd to 4th week of gestation, for approximately 33 to 35 weeks.

65 Progesterone is preferably administered to a pregnant woman starting as soon as the onset of pregnancy and whose cervix is longer than approximately 1.0 cm, or more preferably greater than 1.5

fifteen

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Four. Five

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cm. More preferably, progesterone is administered to a pregnant woman beginning as soon as the onset of pregnancy and whose cervix is at least about 1.0 cm long and at most less than or equal to 3.0 cm or less than or equal to 2.5 cm in more preferable embodiments.

The concentration of progesterone is from about 0.01% to about 50%, preferably from about 1% to about 40%, more preferably from about 2.5% to about 30%, even more preferably from about 5% to about 20% , and even more preferably from about 6% to about 15%. In the most preferred embodiments, the concentration of progesterone is from about 7% to about 9%.

In some embodiments, the amount and concentration of progesterone must be sufficient to remain in the subject to perform prophylaxis or treatment, for example for about 1 hour or more, preferably more than about 2 hours, even more preferably more than 6 hours. , even more preferably more than about 12 hours, even more preferably more than about 24 hours, and most preferably more than about 36 hours.

In some embodiments, progesterone is supplied in solution, such as an oil or other suitable vehicle as will be understood by those skilled in the art. Other methods of administration, such as oil-based capsules and suppositories, are also available in some embodiments. In suppositories, any traditional binder and / or vehicle can be used, for example, one or more polyalkalen glycols or triglycerides; such suppositories can be formed from mixtures containing the active ingredient preferably in the range of about 0.5% to 10%, more preferably about 1 to 2%.

Embodiments of the present invention administer progesterone as many times per day as necessary to be effective in preventing and / or treating premature births, that is, delaying labor and increasing gestation, preferably more or equal to 37 weeks. In some variations of these embodiments, the dose of progesterone is 1 to 4 times a day. Those skilled in the art will understand that the frequency of administration per day varies according to the concentration and amount of progesterone administered. For example, the administration systems of 90 mg of progesterone at 8% are preferably administered once a day. In other embodiments, 200 mg of progesterone is administered 2 to 4 times a day.

Some embodiments of the present invention administer progesterone in conjunction with or in a composition having a pharmaceutically acceptable bioadhesive carrier that includes a crosslinked carboxylic polymer. Some variations of these embodiments include a water-swellable polycarboxylic acid polymer, which, upon administration, provides direct local tissue levels and efficacy without harmful blood levels of the treatment agent.

The compositions of the present invention are useful for vaginal administration. The vaginal route of administration is chosen because of its potential for greater patient satisfaction compared to an intramuscular dose, and for greater efficacy through improved administration of medication to the desired tissues. It has been found that the bioadhesive formulations of the invention perform local vaginal administration of useful local progesterone levels, while avoiding levels that cause undesirable side effects. Vaginal administration also avoids first-pass metabolism problems, for example, it provides a first effect of uterine passage, and direct administration to the uterus allows lower systemic concentrations of the drug.

In preferred embodiments, the progesterone is administered in a bioadhesive progesterone formulation for vaginal application consisting of a polycarbophilic gel containing 8% (w / w) progesterone. In the most preferred embodiments, progesterone is administered as 8% progesterone gel and placebo, which can easily be obtained as Prochieve® or Replens®, manufactured by Columbia Laboratories, Inc., NJ. In some embodiments, the progesterone is administered in a single-use disposable prefilled plastic applicator, which administers the dose of 1,125 g of gel containing 90 mg of progesterone. Embodiments of the present invention administer progesterone according to U.S. Patent No. 5,543,150 from U.S. Patent Application No. 08 / 122,371, which is incorporated herein in its entirety.

The described composition of the present invention can be used in conjunction with other methods of preventing and / or treating premature birth and / or short cervix in pregnant women, such as surgical cerclage, administration of complementary / supplementary compositions such as antibiotics, indomethacin, and polymeric compositions, for example. Accordingly, the present invention is suitable for combination therapy.

Examples

The present invention is best illustrated with the following examples. Although the results of the study show that progesterone can be effectively administered to pregnant women who have base cervix lengths between approximately 1.0 cm and 8.0 cm to treat or prevent cervical length decrease during pregnancy, and so on. To treat or avoid the onset of premature birth and premature birth, the following examples show increased efficacy in specific subgroups of women with a short cervix as defined in the claims.

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Example 1a. Randomized, double-blind, placebo-controlled trial of the effects of progesterone on premature birth

5 In light of the current technique, a study was conducted to examine the effects of progesterone on premature birth and premature birth in women with a history of a previous premature birth. The baseline data for the study are shown in Figure 1. The participants in the study were 611 evaluable pregnant women, of which 308 were selected for a treatment group and another 302 for a placebo group. The selection, categorization and decomposition of the two groups is outlined in the flowchart of Figure 2. The study was a prospective, randomized, placebo-controlled, double-blind, multicenter trial in pregnant women at high risk of spontaneous premature birth. . Participants in the study were classified as 16.0/7 and 22 6/7 weeks of gestational age. Participants were randomized to medication or placebo from 18/7 to 22/6 weeks.

15 Participants who met the study criteria were selected by the researcher between 18 0/7 and 22 6/7 weeks and received vaginal gel of progesterone or placebo packaged identically, sequentially numbered in a ratio of 1: 1. For the variable block size, a SAS procedure (SAS Institute Inc., Cary, NC, United States of America) was used to generate a randomized program stratified by place of study and by inclusion criteria (previous premature birth or short cervix) . Quintiles, Inc. (Kansas City, MO, United States of America) generated the randomization sequences, which were confidentially supplied to the packaging company. The treatment allocation was hidden by an identical packaging and labeling process carried out by Aptuit, Inc. (Mount Laurel, NJ, United States of America). Study patients, obstetric care providers, study researchers, coordinators of the

25 study and study supervisors did not know the exposure status (progesterone or placebo) of the study patients.

Once randomized, participants began treatment with the study medication assigned and administered daily up to 37 weeks of gestational age, development of premature rupture of membranes, or delivery. Participants were randomized at a 1: 1 ratio to receive PROCHIEVE® 8% (90 mg natural progesterone gel administered vaginally) or placebo vaginal gel. All women performed daily self-dosing of their assigned study medication, PROCHEIVE® (progesterone) or placebo.

Example 1b Follow-up on the randomized, double-blind, placebo-controlled trial of the effects of 35 progesterone in premature birth

The data presented in this example provides a further examination of the data presented in example 1a. The objective of this trial was to determine whether prophylactic administration of vaginal progesterone reduces the risk of premature birth in women with a history of spontaneous premature birth.

This trial was a randomized, double-blind, placebo-controlled, multinational trial in which 659 pregnant women with a history of spontaneous premature birth alone were randomized. Between 18.0/7 and 22 6/7 weeks of gestation, patients were randomly assigned to once-daily treatment with 8% progesterone vaginal gel or placebo until delivery, 37 weeks of gestational age, or development of

45 premature rupture of membranes (PROM). The primary outcome was premature birth at ≤ 32 weeks gestation. Statistical analysis was made based on the principle of attempted treatment.

Pregnant women were eligible to participate in the trial if they were between 18 and 45 years of age with an estimated gestational age between 16 0/7 and 22 6/7 weeks, and had a history of single spontaneous premature birth between 20 0 / 7 and 35 0/7 weeks gestation in the immediately preceding parity confirmed by review of medical records of the qualifying premature birth. Patients also had to understand English or a common local language, voluntarily sign an informed consent form, demonstrate that they understood the purpose of the study, and agree to their participation in the study protocol.

55 Patients were excluded from the trial if they had a history of adverse reaction to progesterone or any component present in the treatment medication; had received treatment with progesterone within 4 weeks prior to participation; or were currently being treated for an epileptic disorder, psychiatric disorder, or chronic hypertension in enrollment. Patients who had a history of acute or chronic congestive heart failure, renal failure, or uncontrolled diabetes mellitus were also excluded from the trial; an active liver disorder; HIV infection with a CD4 count <350 cells / mm3 and requiring multiple antiviral agents; a placenta previa or low placenta that requires vaginal precautions; a history or suspicion of malignancy of the breast or genital tract; a history or suspicion of thromboembolic disease; or a disease of Müller. Nor were patients enrolled or previously enrolled in another research study within 1 month prior to selection for this study. I also know

65 limited participation in the trial to patients if the present pregnancy was complicated by a major fetal anomaly or a known chromosomal disorder, or if it was a multifetal pregnancy. Patients with cerclage

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placed cervical, or those who tried to have one placed during the current pregnancy, were excluded from participation in the study, as well as those who had signs of premature rupture of membranes, vaginal bleeding, amnionitis, or premature delivery when enrolled. Finally, patients who could not or did not want to follow the study procedures or had a qualifying premature delivery produced without premature delivery were not included in the study.

The study medication was packaged and labeled according to the 1: 1 randomization scheme provided by Quintiles, Inc (Kansas City, MO, United States of America). A SAS procedure (SAS Institute Inc., Cary, NC, United States of America) was used for variable block size to generate the stratified randomization program by place of study. Thirty-three of the 53 centers completed at least 1 randomized block, which accounted for 92% of enrolled patients. The study drug (Prochieve® 8% progesterone gel) and placebo (Replens®) were supplied by Columbia Laboratories, Inc. (Livingston, NJ, United States of America). Patients were asked to self-administer the complete vaginal gel applicator at approximately the same time each day, preferably in the morning. Patients received a 2-week supply of the treatment assigned at the time of randomization, and at each study visit the following two weeks. At each visit they had to carry all the medication supplies in all the study centers, and compliance with the study medication was determined from the empty containers returned and the unused ones. Percentage compliance was assessed as total duration of treatment: (total applicators used / days of total doses) x 100. Days of total doses were defined as the interval from enrollment to the date of rupture of premature delivery membranes, the date of premature birth without rupture of membranes, or gestation of 37 0/7 weeks.

The occurrence of adverse events was investigated in the visit every 2 weeks in all centers asking if the patient had complaints or problems. Participants received an additional medication supply for 1 week at the start of treatment in case they could not attend the next regularly scheduled appointment. The drug prepared from the study is a bioadhesive progesterone formulation for vaginal application consisting of a polycarbophil-based gel containing 8% (w / w) progesterone. A disposable pre-filled plastic applicator, for single use, administers the dose of 1,125 g of gel containing 90 mg of progesterone. The placebo was Replens®, the bioadhesive administration system without progesterone.

The investigator or the study coordinator selected participants with a documented history of spontaneous premature birth between 16/7/22 and 6/7 weeks of gestation. Gestational age was based on the last menstrual period of the patient and was correlated with an ultrasound biometrics algorithm. Each patient underwent at least one ultrasound examination before randomization to confirm gestational age and exclude significant abnormalities of the fetus, and a transvaginal examination to determine the length of the cervix. Participants who met the study criteria were selected by the researcher between 18 0/7 and 22 6/7 weeks to receive blind study medication. After randomization, the patient began daily treatment and continued it until the gestational age of 37 0/7 weeks, the appearance of premature rupture of the membranes, or premature birth. Each patient was evaluated at intervals of 2 weeks. At 28 weeks gestation all participants underwent another transvaginal ultrasound examination to determine cervical length.

The baseline characteristics were similar in the two treatment groups. Progesterone did not decrease the frequency of premature birth in ≤ 32 weeks. There was no difference in the average gestational age at birth, the morbidity or mortality of the baby, or other measurement of maternal or neonatal outcome. Adverse events due to treatment were similar in the two groups.

Based on these results, prophylactic treatment with vaginal progesterone gel does not effectively reduce the frequency of recurrent premature births in high-risk women selected by a history of spontaneous premature birth. Other risk determination methods must be studied.

A determination of the exact number of pre-examined patients in the 53 study centers, including the offices of reference to these places, was not considered feasible. An estimate of 1500 pre-examined participants was obtained by consulting the study centers. A total of 711 women were defined as formally selected (informed consent was obtained, but not randomized), and 42 were subsequently excluded. The most common reasons for exclusion after consent were planned cerclage, comorbid conditions, and not documenting the previous spontaneous premature birth at a qualifying gestational age. A total of 669 patients were considered eligible for enrollment in the study, 659 being randomized in the two treatment groups indicated by maternal history alone (Figure 2). Nine patients enrolled in the planned secondary investigation of the short cervix alone and one qualified patient out of follow-up before randomization were excluded from the analysis. Patients who took at least one dose of study medication and indicated a due date were included in the treatment attempt population. Patients without due date were considered out of follow-up.

The ITT population of preterm patients included 309 patients in the progesterone group and 302 patients in the placebo group. Randomization provided treatment groups well adapted for age, ethnicity, and body mass index (BMI). Parity, the number of previous premature births, and spontaneous abortions were also similar. The mean gestational age (± SD) at randomization was 19.9 (± 2.1) and 20.1 (± 3.3) weeks for the progesterone and placebo groups, respectively. Regarding the history of previous pregnancies, 76.4% of the progesterone patients and 74.5% of the placebo patients had a

image8

5 previous spontaneous premature birth, and 23.6% and 25.5% of the participants in each group had two or more previous preterm births, respectively.

The rate of premature births at ≤ 32 0/7 weeks of gestation, the primary outcome, was not significantly different; 10.0% (n = 31) in the progesterone group and 11.3% (n = 34) in the placebo group. In the analysis of the primary outcome by country / region, there was no significant difference between the country or region observed. The average gestational age at delivery was 36.6 weeks for both progesterone and placebo groups. The compliance rates of the study medication were also similar: 96.2% of women in the progesterone group and 96.4% of women in the placebo group.

15 Other results of the study also did not differ between the progesterone and placebo groups. The preterm birth rate was 41.7% (n = 129) versus 40.7% (n = 123), respectively, at <37 0/7 weeks; 22.7% (n = 70) versus 26.5% (n = 80), respectively, at ≤ 35 0/7 weeks; and 3.2% (n = 10) versus 3.0% (n = 9), respectively, at ≤ 28 0/7 weeks. Survival curves for delivery time are shown in Figure 5a. Admissions for preterm birth (25.6% compared to progesterone versus 24.8% for placebo), administration of tocolytic medications, and administration of corticosteroid therapy before delivery were similar between the two groups. In patients admitted for preterm birth treatment, the number of days from admission to delivery was 30 for progesterone and 19.6 for placebo (95% CI, -23-2.3). In addition, there were no differences in the rate of premature rupture of membranes (12.0% vs. 12.6%) or delivery with dead product / intrauterine fetal death (1.6% vs. 1.3%) in the groups of progesterone and placebo, respectively.

25 The average birth weight of infants in the progesterone and placebo groups was similar (2680 ± 710 versus 2661 ± 738 gm, respectively), as well as head circumference (32.3 ± 3.34 versus 32 , 5 ± 3.75 cm, respectively). There were no differences between the treatment and placebo groups for APGAR scores of 1 minute (mean score = 8 for each) and 5-minute (mean score = 9 for each), or the admission rate in the neonatal intensive care unit ( 17.5% vs. 21.5%). Cases of neonate respiratory distress syndrome (11.0% vs. 11.9%), grade 3 or 4 intraventricular hemorrhage (0.3% vs. 0.3%), and necrotizing enterocolitis (1.0% versus 1.7%) were also similar for the progesterone and placebo groups. Potentially acquired congenital anomalies were observed in the second or third trimesters in 2 newborns: 1 case of hip subluxation and pulmonary stenosis in each group. Developmental anomalies were not included.

35 related to first trimester organogenesis, such as hypospadias, extra fingers, and tetralogy of Fallot. Baby tracking data for 6, 12, and 24 months of age are still being collected and are not available at the time of reporting these results.

Example 2. Randomized trial investigating the efficacy of vaginal progesterone for the prevention of early premature birth in women with shortened cervix in the middle of the trimester

The study also included women with no history of premature birth and with a short cervix at the time of enrollment. Although the short cervical population only included 9 patients, the results suggested a possible effect of progesterone with 40% (2/5) of deliveries ≤ 32 weeks of gestation in placebo and 0 (0/4) deliveries ≤ 32

45 weeks gestation in progesterone. Since some participants with a history of previous premature birth also had a short cervix, the study's premature birth population was divided into quartiles based on cervical length. The lowest quartile (≤ 3.2 cm) was combined with short cervical patients only and subdivided sequentially and primary and secondary outcomes were analyzed for women with cervical lengths of ≤ 3.0 cm and <2.8 cm at the same time of enrollment. There were an insufficient number of patients with even shorter cervical lengths available for further analysis. For the purposes of the study, the criteria for short cervix were established at less than 2.8 cm. A total of 46 participants fell into this category, and its demography and characteristics are shown in Figure 3.

Overall, a cervical length <2.8 cm was identified in 46 randomized women: 19 of 313 received

55 progesterone and 27 of 307 received placebo. The base characteristics of the two groups were similar. The premature birth rate at ≤ 32 weeks was significantly lower for progesterone than for placebo (0% vs. 29.6%, P = 0.014). With progesterone, there was less income in the NICU (15.8% vs. 51.9%, P = 0.016) and shorter stays in NICU (1.1 vs. 16.5 days, P = 0.013). There was also a trend towards a lower rate of neonatal respiratory distress syndrome (5.3% versus 29.6%, P = 0.060). It was determined that vaginal progesterone gel reduces the rate of premature premature birth and improves the neonatal outcome in women with cervical shortening in the mid-trimester.

The study included women with a documented history of spontaneous premature birth (<35 weeks) in a single pregnancy in the immediate preceding parity regardless of cervical length, and women without 65 history of premature birth but with cervical shortening in the middle trimester (≤ 2, 5 cm) in the current pregnancy they were offered to enroll in the study at 18 0/7 -22 6/7 weeks gestation. Recruitment began in April of

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2004 and the last patient gave birth on January 8, 2007.

Women who, prior to selection, had a pregnancy condition or complication that increased the maternal or fetal risk of an adverse outcome, significantly increased the risk of premature birth due to medical (non-spontaneous) indication, or probably it would result in lack of observance or early interruption of the study. Therefore, women who had any of the following conditions were excluded: age <18 or> 45 years; multifetal pregnancy; history of adverse reaction to progesterone or any component present in the treatment medication; progesterone treatment within 4 weeks before enrollment; or current treatment of an epileptic disorder, psychiatric disorder, or chronic hypertension. Patients who had a history of acute or chronic congestive heart failure, renal failure, or uncontrolled diabetes mellitus were also excluded from the trial; an active liver disorder; an HIV infection with a CD4 count <350 cells / mm3 and requiring multiple antiviral agents; a placenta previa or placenta falls and subjected to vaginal precautions; a history of malignancy of the breast or genital tract; a thromboembolism; or a disease of Müller. We did not include patients who currently or previously had participated in another research study within one month before randomization.

The participation of patients in the trial was also limited if the present pregnancy was complicated by a major fetal abnormality or a known chromosomal abnormality. Patients with cervical cerclage, or those who wanted to have one placed during the current pregnancy, were excluded from the study, as well as those who had signs of premature rupture of membranes, vaginal bleeding, amnionitis, or premature delivery when enrolled.

Women with a history of spontaneous premature birth in the previous pregnancy regardless of cervical length or women without a history of premature birth but with cervical shortening at mid-trimester in the current pregnancy were selected by the investigator or the study coordinator between 16 0/7 and 22 6/7 weeks gestation. The previous history of spontaneous premature birth was confirmed by evaluation of the patient's medical records before enrollment. Gestational age was based on the last menstrual period of the patient and was correlated with an ultrasound biometrics algorithm. Each patient underwent at least one ultrasound examination before randomization to confirm gestational age and exclude major fetal abnormalities, and a transvaginal examination to determine the length of the cervix. Participants who met the study criteria were enrolled by the researcher between 18 0/7 and 22 6/7 weeks and received vaginal gel of progesterone or placebo packaged identically, sequentially numbered in a ratio of 1: 1. A SAS procedure (SAS Institute Inc., Cary, NC, United States of America) was used for variable block size to generate a randomized program stratified by place of study and by inclusion criteria (previous premature birth or short cervix). Quintiles, Inc. (Kansas City, MO, United States of America) generated the randomization sequences, which were confidentially supplied to the packaging company. The treatment allocation was hidden by an identical packaging and labeling process carried out by Aptuit, Inc. (Mount Laurel, NJ, United States of America). Study patients, obstetric care providers, study researchers, study coordinators, and study supervisors were blind to the exposure status (progesterone or placebo) of all study patients.

After randomization, the patient began daily treatment and continued until gestational age of 37 0/7 weeks, the appearance of premature rupture of membranes, or delivery. Each patient was evaluated at intervals of 2 weeks. All participants underwent another transvaginal ultrasound examination to determine cervical length at 28 weeks gestation.

Before starting the study, base measurements of the cervical length of each participant were taken and are shown in Figure 1. During the study, cervical length measurements were made by ultrasound both at the base and later at 28 weeks after A 6-10 week dose period. The average cervical length of 3.7 cm was the same for both treatment and placebo groups, and the cervical length range for all participants was between 1.1 cm and 7.9 cm. At 28 weeks gestation, the cervix of each participant was measured again and the data were compared with the base data, and an unexpected and surprising conclusion was reached. As shown in Figure 4, the average decrease in cervical length after 28 weeks for participants in the placebo group was 0.61 cm, while the average decrease in cervical length in the same period of time for participants in the treatment group (that is, in the progesterone regimen) it was only 0.44 cm. Since the value for the general trial was 0.038, the results indicate that there was a statistically significant decrease in the amount of shortening or obliteration of cervical length for women in the progesterone regimen compared to women who took placebo.

The results of the study are illustrated using Kaplan-Meier curves as depicted in Figures 5b-10, examining the endpoint of premature birth in the study. Figure 5b is a time curve until delivery for all randomized patients. Although the curves for each group in Figure 5b appear to have substantial overlap, when the results are further broken down for analysis by cervical length of the patient based, the difference in outcome between the treatment and placebo groups is clearly visible. For patients who have a cervical base length less than or equal to 3.2 cm, (figure 6), less than or equal to 3.0 cm (figures 8 and 9), and less than 2.8 cm (figure 10), participants in the treatment group clearly showed a probability of non-delivery in a longer gestation period compared to the participants in the placebo group. As shown in Figure 7, no statistically significant difference in outcome was reflected between the treatment and placebo groups in patients with a cervical base length greater than 3.2 cm at baseline.

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5 With reference to Figure 10, which shows the probability that patients with a base cervical length of less than 2.8 cm who still do not give birth, the group of participants that had a cervical length of less than 2.8 cm experienced a significant reduction in the frequency of premature birth. As shown in Figure 10, among 46 participants (19 treated with progesterone, for example, Prochieve® brand progesterone, and 27 placebo) the frequency of premature birth in the treatment group was 0%, compared to 29.6% in the placebo group (P =

10 0.014). For the purposes of this study, the premature birth parameter was set less than or equal to 32 weeks. Figure 11 includes a more detailed decomposition of labor at various points of gestation for the progesterone and placebo groups, namely for less than or equal to 37, 35, 32 and 28 weeks. The result was markedly better in the treatment group compared to the placebo group at each time point. Specifically, for less than or equal to 37 and less than 35 weeks, the treatment reduced the number of births

Approximately 15 premature babies in half, and for less than or equal to 32 and less than or equal to 28 weeks, there were no premature births in the treatment group, although there were 8 and 3 premature births, respectively, in the placebo group.

The results of the study also revealed an improved outcome of infants born to participants in the

20 progesterone group, shown in Figure 12. When administered to women with a cervical length <2.8 cm, progesterone therapy reduced the number of admissions in the NICU (15.8% versus 51.9 %, P = 0.016) and decreased the length of stay in the NICU (1.1 vs. 16.5 days, P = 0.013). There was a tendency to reduce the total number of hospital days of neonates (5.8 versus 18.2 days, P = 0.055) and decreased the occurrence of neonatal respiratory distress syndrome (5.3% versus 29.6 %, P = 0.060) with progesterone therapy.

25 In the subgroup of women enrolled with a cervical length of <2.8 cm, there were 2 deaths of the fetus / baby in the placebo group ([1] term, died at 11 months of age, SIDS; [2] 35 weeks gestation, aspiration pneumonia) and none in the vaginal progesterone group.

30 Based on the results of this study, it is evident that the administration of progesterone to pregnant women effectively decreases the amount of shortening or erasure of their cervix, most notably in women with short cervix.

Example 3. Population with a base cervical length of ≤ 2.8 cm

35 Data for a subgroup of participants that have a cervical base length less than or equal to 2.8 cm are shown in Table 1 below. The results show that 8 of the 27 participants who received the placebo regimen gave birth before 32 weeks, while none of the 19 participants who received the progesterone regimen gave birth before 32 weeks. As indicated by the two-sided p-value of 0.014 and 95% CI -0.469,

40 0.124, the results indicate the statistically significant effect in reducing births before 32 weeks by administration of progesterone compared to placebo among a population of pregnant women with a cervical base length of ≤ 2.8 cm. See also Figures 12 and 14a-e, which provide a comparison between treatments of patient outcomes that used placebo based on patients who used Prochieve® progesterone.

45 Table 1

Births> 32 weeks

Births ≤ 32 weeks Total

Placebo group

Number 19 8 27

Treatment group

Number 19 0 19

Total

38 8 46

Fisher's exact test p-value

0.014

95% CI

-0,469, -0,124

Example 4. Population that has a base cervical length of ≤ 3.0 cm

50 Data for a subgroup of participants with a cervical base length less than or equal to 3.0 cm are shown in Table 2 below. The results show that 11 of the 58 participants who received the placebo regimen gave birth at 32 weeks or earlier, while only 5 of the 58 participants who received the progesterone regimen gave birth at 32 weeks or earlier. These results are significant according to 95% CI and the p-value.

Two-sided 55 indicates a tendency to reduce births before 32 weeks by administration of progesterone compared to placebo among the population of pregnant women with a cervical base length of ≤ 3.0 cm. See also Figures 13a-e, which provide a comparison between treatments for

results of infants from patients who used placebo based on patients who used Prochieve® progesterone.

Table 2

Births> 32 Weeks

Births ≤ 32 Weeks Total

Placebo group

Number 47 eleven 58

Treatment group

Number 54 4 58

Total

Total

101 fifteen 116

Pr ≤ P two sides

0.094

95% CI

-0.214, -0.001

Claims (7)

image 1 1. A medicine for use in the treatment or prevention of the onset of premature labor and subsequent premature birth in a pregnant woman with a short cervix of 1.0 cm to 3.0 cm, where the medicine includes 5 progesterone and has been formulated to administer a dose of between 90 mg and 250 mg of progesterone in order to minimize the shortening of the cervix, and where the medication has been formulated for administration vaginally or intravaginally. 2. A medicament for use according to claim 1 in the form of a vaginal gel, a vaginal suppository, a vaginal cream or a solid vaginal dosage form.

3.

 A medicament for use according to any of the preceding claims, for daily administration.

Four.

 A medicament for use according to any of the preceding claims, for administration (a) of the 18th to

15 the 22nd week of gestation until the 37th week of gestation; or (b) over a period of 14 to 19 weeks; or (c) from the 16th week of gestation to the 37th week of gestation; or (d) over a period of 21 weeks; or (e) from the time of a positive pregnancy test until the 37th week of gestation; or (f) from the 2nd to the 4th week of gestation; or (g) for 33 to 35 weeks. A medicament for use according to claim 3, for administration depending on the gestational age at the start of the treatment and the date of delivery. 6. A medicament for use according to any of the preceding claims, which is in the form of, or is contained in in, a medicament delivery system including progesterone, a crosslinked polycarboxylic acid polymer, water swellable, water soluble, and at least one adjuvant. 7. A medicament for use according to any of the preceding claims, which is formulated to administer a dose of 90 mg of progesterone. A medicament for use according to any one of the preceding claims, which further improves neonatal morbidity and mortality in a premature neonate expected by, or subsequently born of, the pregnant woman with the short cervix. 9. A medicament for use according to any of the preceding claims, intended for administration in 35 combination with one or more compounds for the treatment or prophylaxis of premature birth, or with a clinical procedure for the treatment or prophylaxis of premature birth. fifteen